Mitch Leslie in Science:
As we get older, senescent cells build up in our tissues, where researchers think they contribute to illnesses such as heart disease, arthritis, and diabetes. In the past, scientists have genetically modified mice to dispatch their senescent cells, allowing the rodents to live longer and reducing plaque buildup in their arteries. Such genetic alterations aren’t practical for people, but researchers have reported at least seven compounds, known as senolytics, that kill senescent cells. A clinical trial is testing two of the drugs in patients with kidney disease, and other trials are in the works. However, current senolytic compounds, many of which are cancer drugs, come with downsides. They can kill healthy cells or trigger side effects such as a drop in the number of platelets, the cellular chunks that help our blood clot. Cell biologist Peter de Keizer of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues were investigating how senescent cells stay alive when they uncovered a different strategy for attacking them. Senescent cells carry the type of DNA damage that should spur a protective protein, called p53, to put them down. Instead, the researchers found that a different protein, FOXO4, latches onto p53 and prevents it from doing its duty.
To counteract this effect, De Keizer and colleagues designed a molecule, known as a peptide, that carries a shortened version of the segment of FOXO4 that attaches to p53. In a petri dish, this peptide prevented FOXO4 and p53 from hooking up, prompting senescent cells to commit suicide. But it spared healthy cells. The researchers then injected the molecule into mutant mice that age rapidly. These rodents live about half as long as normal mice, and when they are only a few months old, their fur starts to fall out, their kidneys begin to falter, and they become sluggish. However, the peptide boosted the density of their fur, reversed the kidney damage, and increased the amount of time they could scurry in a running wheel, the scientists report online today in Cell. When the researchers tested the molecule in normal, elderly mice, they saw a similar picture: In addition to helping their kidneys and fur, the molecule also increased their willingness to explore their surroundings.